Oncotarget

Research Papers:

Mutant TP53 modulates metastasis of triple negative breast cancer through adenosine A2b receptor signaling

Eisuke Horigome, Michiru Fujieda, Tadashi Handa, Ayaka Katayama, Masashi Ito, Ami Ichihara, Daiki Tanaka, Navchaa Gombodorj, Shinji Yoshiyama, Arito Yamane, Keiichi Yamada, Jun Horiguchi, Kazuo Shinozuka, Tetsunari Oyama, Masahiko Nishiyama and Susumu Rokudai _

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Oncotarget. 2018; 9:34554-34566. https://doi.org/10.18632/oncotarget.26177

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Abstract

Eisuke Horigome1,*, Michiru Fujieda1,*, Tadashi Handa2, Ayaka Katayama2, Masashi Ito1, Ami Ichihara1, Daiki Tanaka1, Navchaa Gombodorj1, Shinji Yoshiyama1, Arito Yamane1, Keiichi Yamada3, Jun Horiguchi4, Kazuo Shinozuka3, Tetsunari Oyama2, Masahiko Nishiyama1 and Susumu Rokudai1

1Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan

2Department of Diagnostic Pathology, Gunma University, Gunma, Japan

3Division of Molecular Science, Gunma University, Gunma, Japan

4Department of Breast Surgery, Graduate School of Medical Sciences, International University of Health and Welfare, Chiba, Japan

*These authors contributed equally to this work

Correspondence to:

Susumu Rokudai, email: srokudai@gunma-u.ac.jp

Keywords: ADORA2B; TP53; NF-kB; breast cancer; synthetic lethality

Received: May 02, 2018     Accepted: September 17, 2018     Published: October 02, 2018

ABSTRACT

Purpose: The identification of genes with synthetic lethality in the context of mutant TP53 is a promising strategy for the treatment of basal-like triple negative breast cancer (TNBC). This study investigated regulators of mutant TP53 (R248Q) in basal-like TNBC and their impact on tumorigenesis.

Experimental Design: TNBC cells were analyzed by RNA-seq, and synthetic-lethal shRNA knock-down screening, to identify genes related to the expression of mutant TP53. A tissue microarray of 232 breast cancer samples, that included 66 TNBC cases, was used to assess clinicopathological correlates of tumor protein expression. Functional assays were performed in vitro and in vivo to assess the role of ADORA2B in TNBC.

Results: Transcriptome profiling identified ADORA2B as up-regulated in basal-like TNBC cell lines with R248Q-mutated TP53, with shRNA-screening suggesting the potential for a synthetic-lethal interaction between these genes. In clinical samples, ADORA2B was highly expressed in 39.4% (26/66) of TNBC patients. ADORA2B-expression was significantly correlated with ER (P < 0.01), PgR (P = 0.027), EGFR (P < 0.01), and tumor size (P = 0.037), and was an independent prognostic factor for outcome (P = 0.036). In line with this, ADORA2B-transduced TNBC cells showed increased tumorigenesis, and ADORA2B knockdown, along with mutant p53 knockdown, decreased metastasis both in vitro and in vivo. Notably, the cytotoxic cyclic peptide SA-I suppressed ADORA2B expression and tumorigenesis in TNBC cell lines.

Conclusions: ADORA2B expression increases the oncogenic potential of basal-like TNBC and is an independent factor for poor outcome. These data suggest that ADORA2B could serve as a prognostic biomarker and a potential therapeutic target for basal-like TNBC.


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